In recent years, microRNAs (miRNAs, miRs) have emerged as an important novel class of regulatory RNA, which has profound impact on a wide array of biological processes. These small (typically 18-24 nucleotides long) non-coding RNA molecules can modulate protein expression patterns by promoting RNA degradation, inhibiting mRNA translation, and also affecting gene transcription. MiRs play pivotal roles in diverse processes such as development and differentiation, control of cell proliferation, stress response and metabolism. There are currently about 700 known human miRs, and their number probably exceeds 800.
The expression of many miRs was found to be altered in numerous types of human cancer, and in some cases strong evidence has been put forward in support of the conjecture that such alterations may play a causative role in tumor progression. Cancer-associated changes in miR expression patterns can be brought about by various genetic and epigenetic mechanisms. Most notably, a number of transcription factors whose activity is altered in cancer cells, including c-myc and E2F, were found to regulate the RNA polymerase II-dependent transcription of the precursors of particular miRs. Hence, the oncogenic effects of these transcription factors may be mediated not only by modulation of protein-coding mRNA levels but also by specific changes in miR expression.
The p53 protein is a sequence-specific transcription factor that functions as a major tumor suppressor in mammals. p53 is activated in response to a variety of stress signals, including genotoxic damage, dysfunction of the mitotic apparatus, aberrant activation of oncogenes, oxidative stress, nutrient deprivation and more. The activated p53 can dictate a plethora of biochemical and biological outcomes, ranging from effective repair of minor damage all the way to cessation of cell cycle progression and induction of replicative senescence and apoptotic cell death. Inactivation of the tumor suppressor function of p53 is one of the most frequent genetic alterations in human cancer, and close to half of all human tumors carry p53 gene mutations within their cells.
As a transcription factor, p53 can increase or repress the transcription of many hundreds of protein-encoding genes, and this ability is believed to underlie in great part its tumor suppressor functions.
To date there has been no definitive description of any miR whose expression is directly regulated by p53, or of the functional consequences of such regulation.
In view of the important role of cell death in developmental processes, in normal function and in the pathogenesis of diverse diseases and conditions, there is an increasing need for novel methods of modulating cell death in cell populations and for compositions that may be effectively employed in such methods.